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The mitochondrial single-stranded DNA binding protein is essential for initiation of mtDNA replication

Lookup NU author(s): Dr Thomas NichollsORCiD

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Abstract

We report a role for the mitochondrial single-stranded DNA binding protein (mtSSB) in regulating mitochondrial DNA (mtDNA) replication initiation in mammalian mitochondria. Transcription from the light-strand promoter (LSP) is required both for gene expression and for generating the RNA primers needed for initiation of mtDNA synthesis. In the absence of mtSSB, transcription from LSP is strongly up-regulated, but no replication primers are formed. Using deep sequencing in a mouse knockout model and biochemical reconstitution experiments with pure proteins, we find that mtSSB is necessary to restrict transcription initiation to optimize RNA primer formation at both origins of mtDNA replication. Last, we show that human pathological versions of mtSSB causing severe mitochondrial disease cannot efficiently support primer formation and initiation of mtDNA replication.

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Author(s): Jiang M, Xie X, Zhu X, Jiang S, Milenkovic D, Misic J, Shi Y, Tandukar N, Li X, Atanassov I, Jenninger L, Hoberg E, Albarran-Gutierrez S, Szilagyi Z, Macao B, Siira SJ, Carelli V, Griffith JD, Gustafsson CM, Nicholls TJ, Filipovska A, Larsson NG, Falkenberg M

Publication type: Article

Publication status: Published

Journal: Science Advances

Year: 2021

Volume: 7

Issue: 27

Online publication date: 02/07/2021

Acceptance date: 20/05/2021

Date deposited: 05/07/2021

ISSN (print): 2096-5958

ISSN (electronic): 2375-2548

Publisher: AAAS

URL: https://doi.org/10.1126/sciadv.abf8631

DOI: 10.1126/sciadv.abf8631

PubMed id: 34215584

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